Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccccc3Cl)ccc12
Yield: 92.9 %

Procedure:
853 mg of 2-chlorophenylboronic acid, 30 cm3 of water, 964 mg of sodium carbonate and 252 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared as described in Example 51, in 60 μm3 of dioxane. The reaction medium is then refluxed for 18 hours and filtered through a sinter funnel packed with Celite, and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 70 cm3 of ethyl acetate and the organic phase is washed with 2×30 cm3 of distilled water and then with 30 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 1 g of N-[6-(2-chlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow wax.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:32][CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35].Cl>CN(C=O)C.O>[ClH:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=1
Reactant: CN(C)C(=O)CCl
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-{2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4(1H,3H)-quinazolinedione was dissolved in DMF (5 ml) and NaH (60% dispersion in mineral oil) added. After 0.5 hours, 2-chloro-N,N-dimethylacetamide was added and the solution stirred at room temperature for 16 hours. Water and ethyl actetate were added, the organic phase separated, dried and concentrated to an oil. Purification by chromatography (dichloromethane:methanol 95:5) gave an oil which was treated with 1.0 M ethereal hydrogen chloride solution to give the titled product as a solid(0.015 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc(C(=O)O)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
4-Methoxybenzyl alcohol (11.9 mL, 95.2 mmol) was dissolved in DMF (150 mL), and at 0° C., 55% sodium hydride (4.15 g, 95.2 mmol) was added thereto, followed by stirring at room temperature for 1 hour. A DMF (10 mL) solution of 6-chloronicotinic acid (5.00 g, 31.7 mmol) was added to the reaction mixture, followed by stirring at 80° C. for 2 hours. Water (200 mL) was added to the reaction mixture, and 4 mol/L hydrochloric acid (30 mL) was added dropwise thereto, and the precipitated solid was collected by filtration to afford 6-(4-methoxybenzyloxy)nicotinic acid (8.15 g, 99%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[C:26]([C:32](O)=[O:33])=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:26]3[C:25]([Cl:24])=[CH:30][C:29]([Cl:31])=[CH:28][N:27]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: C[C@@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 3,5-dichloro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH:18]([OH:19])[CH2:17][N:16]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([O-])(=O)C.[NH4+]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:16]2[CH2:15][CH:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]([OH:19])[CH2:17]2)=[O:28])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CN(C(=O)c3ccc(Cl)cc3)CC2O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCNCC2)C1
Yield: 99 %

Procedure:
The desired compound was prepared according to Boc deprotection procedures described generally above from 4-[1-(4-Chloro-benzoyl)-4-hydroxy-pyrrolidin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester in 99% yield. 1H-NMR (300 MHz, D2O): δ 2.75 (1H, m), 3.0 (1H, m), 3.15 (4H, m), 3.25 (3H, m), 3.3-3.5 (2H, m), 3.7 (1H, m), 3.9 (1H, m), 4.4 (1H, m), 7.35 (4H, dd). Retention Time (LC, method: ammonium acetate standard): 0.89 min. MS (M+H+): 310
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[F:49]C1C=CC=CC=1N>C(O)(=O)C>[F:49][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: Nc1ccccc1F
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1F
Yield: 26 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 2-fluoroaniline (88.6 mg, 0.8 mmol), and acetic acid (0.12 ml) were used to give 36 mg (0.11 mmol, 26% yield) of the title compound.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH2:5][CH2:4][CH:3]=1.[H-].[Na+].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].O>CN(C)C=O>[CH2:25]([O:7][CH2:1][C:2]1[O:6][CH2:5][CH2:4][CH:3]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: OCC1=CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC1=CCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A solution of 4.09 g of 4,5-dihydrofurfuryl alcohol (prepared as described in Preparation 12) in 10 ml of dimethylformamide was added dropwise to 2.62 g of a 55% w/w suspension of sodium hydride in mineral oil, itself suspended in 40 ml of dimethylformamide, whilst maintaining the temperature of the mixture at from 5° to 12° C. by ice-cooling. The mixture was then stirred at room temperature for 30 minutes, 18.32 g of hexadecyl bromide were added to the solution, and the whole was stirred at room temperature for 15 hours. The reaction mixture was then poured into 200 ml of water, and extracted twice with diethyl ether. The extract was washed with water, dried and condensed by evaporation under reduced pressure. The oily residue, 17 g, was subjected to column chromatography through 400 g of Grade II-III alumina (a product of Woelm Pharma, West Germany). The fraction eluted with a 1:20 by volume mixture of diethyl ether and hexane gave 9.512 g of the title compound as a solid, melting at 30.5°-31.5° C. (cold hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:21]([O-])=O)=[CH:5][C:6]([C:17]([F:20])([F:19])[F:18])=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:8]=1.O.O.Cl[Sn]Cl.[OH-].[Na+].C(Cl)Cl>C(O)C.O>[NH2:21][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[O:10])=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1
Reactant: COc1cc(C(=O)N2CCOCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N2CCOCC2)c(C(F)(F)F)cc1N
Temperature: 65 °C
Yield: 79 %

Procedure:
To (5-methoxy-4-nitro-2-(trifluoromethyl)phenyl)(morpholino)methanone (349 mg, 1.04 mmol) in ethanol (20 mL) and water (2 mL) was added SnCl2.2H2O (941 mg, 4.16 mmol). The mixture was heated to 65° C. for 2 h and then 2 M aqueous sodium hydroxide solution (20 mL) and DCM (20 mL) were added. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (250 mg, 79%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=305 at 2.87 min. 1H NMR (400 MHz, CDCl3): δ 6.94 (s, 1H), 6.64 (s, 1H), 4.07 (s, 2H), 3.92-3.67 (m, 4H), 3.89 (s, 3H), 3.62-3.52 (m, 2H), 3.25-3.19 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([C:29]2[O:30][C:31]([C:37]([F:40])([F:39])[F:38])=[C:32]([C:34](O)=[O:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:34]([C:32]3[N:33]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:30][C:31]=3[C:37]([F:39])([F:40])[F:38])=[O:35])=[CH:16][C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2C#N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
Crude 4-(4-amino-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester from above was dissolved in methylene chloride (10 mL) and to the resulting solution was added 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (454 mg), triethylamine (247 μL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 337 mg). The reaction mixture was stirred at room temperature for 3 hr. Another portion of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.5 eq) was added. The reaction mixture was stirred at 50° C. for 3 hr and at room temperature for 3.5 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography afforded 4-{2-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (240 mg, 25% yield) as a yellow solid. LCMS calcd for C27H26F3N5O4 (m/e) 541, obsd 542 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2,4-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][OH:7])[CH2:2][OH:3].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.[OH-:16].[Na+]>CO>[OH:3][CH2:2][CH2:1][N:4]([CH2:5][CH2:6][OH:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:4]([CH2:1][CH2:2][OH:3])[CH2:5][CH2:6][OH:16]
Reactant: OCCNCCO
Reactant: BrCCCCCCBr
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: OCCN(CCO)CCCCCCN(CCO)CCO
Temperature: 57.5 °C
Reaction time: 4 h

Procedure:
N,N-Diethanolamine (1331.3 g, 11.36 mol) is placed in a 5000 ml three-necked round bottomed flask fitted with a condenser, addition funnel, internal thermometer, mechanical stirrer and argon inlet. 1,6-Dibromohexane (1386 g, 5.68 mol) is added via the addition funnel slowly to keep the reaction temperature below 60° C. After addition is completed the mixture is heated to 55-60° C. for 18 h. The reaction mixture is poured into a 6 L Erlenmeyer flask containing a solution of methanol (1.5 L) and sodium hydroxide (227.2 g, 5.68 mol). White salts begin to precipitate. After 4 h, the mixture is filtered. The filtrate is concentrated under reduced pressure to leave the product as a viscous oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:10]=3[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[C:33]([NH:40][CH2:41][C:42](O)=[O:43])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:32][C:30]1[CH:29]=[CH:28][C:10]2[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=[C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:42](=[O:43])[CH2:41][NH:40][C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:7][CH2:6]3)[C:9]=2[CH:31]=1
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(N)CC2)c2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(NC(=O)CNC(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.6 %

Procedure:
5-(4-Aminopiperidin-1-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (15 mg, 0.034 mmol) was dissolved in anhydrous N,N-dimethylformamide (0.3 mL), and Boc-glycine (7 mg, 0.037 mmol), and then 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (8 mg, 0.04 mmol), 1-hydroxybenztriazole (5 mg, 0.04 mmol), and triethylamine (6 μL, 0.04 mmol) were added. The reaction was stirred at ambient temperature for 24 hours. The solution was diluted with ethyl acetate (5 mL), washed with saturated sodium bicarbonate (3×1 mL), dried with sodium sulfate, decanted and concentrated in vacuo. Column chromatography eluting with a gradient of 70-100% ethyl acetate in hexanes provided tert-butyl 2-(1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-ylamino)-2-oxoethylcarbamate (3 mg, 15%). This material was dissolved in dichloromethane (0.2 mL) and trifluoroacetic acid (0.1 mL) and stirred at ambient temperature for 1 hour then concentrate in vacuo. Azeotroping four times with dichloromethane provided 2-amino-N-(1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-yl)acetamide as the trifluoroacetate salt (3 mg, quant. yield). ESI m/z measured 504.2173 [M+H]+. calculated 504.2166.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:22][C@H:21]1[CH2:34][C:35](=[O:37])[NH2:36])=[O:19])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[C:35]([CH2:34][C@@H:21]1[CH2:22][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:24][CH2:25][N:20]1[C:18](=[O:19])[CH2:17][O:16][C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:38])=[O:5])(=[O:37])[NH2:36]
Reactant: CC(C)(C)OC(=O)COc1cc(Cl)ccc1OCC(=O)N1CCN(Cc2ccc(F)cc2)C[C@H]1CC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1OCC(=O)O
Yield: 84.1 %

Procedure:
A solution of (2-{2-[(2R)-2-carbamoylmethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-5-chloro-phenoxy)-acetic acid tert-butyl ester (0.070 g, 0.13 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (0.10 mL) was stirred for 3.5 h and then concentrated. The resulting residue was diluted with dichloromethane and the excess trifluoroacetic acid was quenched with saturated aqueous sodium carbonate. The aqueous layer was neutralized with 0.1N hydrochloric acid and extracted one time with dichloromethane/methanol (1:1) and twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title compound (0.054 g, LRMS: 492.4, 494.4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11].Cl[CH2:15][O:16][CH2:17][CH3:18].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([O:13][CH2:15][O:16][CH2:17][CH3:18])([CH3:11])[CH3:12]
Reactant: Cc1cc(Br)c(C(C)(C)O)cc1Cl
Reactant: CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOCOC(C)(C)c1cc(Cl)c(C)cc1Br
Temperature: 40 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A mixture of 2-(2-bromo-5-chloro-4-methylphenyl)propan-2-ol (4.5 g 17.1 mmol), (chloromethoxy)ethane (3.2 g, 34.2 mmol) and DIPEA (6.6 g, 51.3 mmol) in DCM (50 mL) was stirred at 40° C. overnight under argon. Water (50 mL) was added and the mixture was extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE-EA (10:1) to give 1-bromo-4-chloro-2-(2-(ethoxymethoxy)propan-2-yl)-5-methylbenzene (4.27 g, yield 77.5%). 1H NMR (400 MHz, DMSO-d6): δ 7.67 (s, 1H), 7.50 (s, 1H), 4.59 (s, 2H), 3.55 (q, 2H), 2.29 (s, 3H), 1.65 (s, 6H), 1.08 (t, 3H) ppm; MS: m/z=344.8 (M+Na+, ESI+).
Reaction SMILES: [CH2:1]([NH:8][C:9](SC)=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>C(#N)C>[CH2:1]([NH:8][C:9]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:24]2[CH:32]=[CH:33][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:31][CH2:30]1)=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C#N)=C(NCc1ccccc1)SC
Reactant: Fc1ccc(CN2CCNCC2)cc1
Solvent: CC#N
Product: CCOC(=O)C(C#N)=C(NCc1ccccc1)N1CCN(Cc2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 21 %

Procedure:
To ethyl 3-benzylamino-3-methylthio-2-cyanoacrylate (1.50 g, 5.43 mmol) and 1-(p-fluorobenzyl)piperazine (2.11 g, 10.9 mmol) was added acetonitrile (1 ml) and the mixture was heated under reflux at 80° C. for 2 hours. The reaction product was purified by silica gel column chromatography to give the title compound as a brown oily substance (0.48 g) from the fraction from hexane-ethyl acetate (1/1). Yield=21%.
Reaction SMILES: [Ag:1].[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([OH:8])=[O:7])[OH:5]>>[Ag:1].[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([O-:8])=[O:7])[OH:5].[Ag+:1]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Ag]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)[O-]
Product: [Ag+]
Reaction time: 0.02 h

Procedure:
Water was introduced into a reverse osmosis unit, passing through a semi-permeable membrane to remove impurities and producing deionized water. Anhydrous 99% pure citric acid was mixed with the water to produce 200 gallons of a 20% (wt/vol) (796 g citric acid per gallon water) solution. The 200 gallons of 20% citric acid were directed into an ion chamber containing having positive and negative electrodes, each consisting of 200 troy ounces of 999 fine silver. The positive and negative electrodes were spaced at least 2.0 mm apart, allowing the citric acid solution to pass between the two electrodes. An ion generation controller (IGC) power supply including a positive and a negative conductor was attached to the positive and negative electrodes. The IGC applied a current of 5 amps at 17 volts, pulsed every 9 seconds, with a polarity change at 1 minute intervals. Throughout the process, the electrode gap was adjusted in order to maintain the 5 amp-17 volt output. The electric current flow caused an ion current to flow between the positive and negative electrodes, producing free silver ions within the diluted citric acid solution. The silver ions reacted with the citric acid in the citric acid solution to produce the silver dihydrogen citrate solution. The 20% citric acid solution was recirculated through the ion chamber at 50 gallons per minute for 144 hours until the desired silver ion concentration was obtained. The silver dihydrogen citrate solution was then allowed to sit in order to allow any solids formed during the procedure to precipitate. The resulting product was a silver dihydrogen citrate solution having a silver ion concentration of 2400 ppm. Hereafter, this solution is referred to as a stock solution. The stock solution can be used immediately per the following examples or stored for later use.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]=[C:10]1O[C:12](=[O:13])[CH2:11]1.C(O)(=O)C.S(=O)(=O)(O)O>C(OCC)(=O)C.O>[CH3:1][N:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]([CH3:9])=[CH:11][C:12]1=[O:13]
Reactant: CNc1ccccc1
Reactant: C=C1CC(=O)O1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)n(C)c2ccccc12
Temperature: 100 °C

Procedure:
The starting 1,2-dihydro-1,4-dimethyl-2-quinolone (3) is prepared by first conjugating N-methylaniline with diketene, followed by an acid cyclization of the amide intermediate. Thus 10.0 g (0.12 moles) of diketene is added dropwise to 10.7 g (0.1 moles) of N-methylaniline and the reaction is heated at 100 ° C. for an additional 30 minutes. To the resulting mixture is added 30 mL of acetic acid and 30 mL of sulfuric acid, and the mixture is heated at 50 ° C. overnight. The reaction is worked up with water and ethyl acetate and purified on a silica gel column to yield 9.5 g of the desired product.